Abstract
Metabolic reprogramming is an essential hallmark of cancer. Besides the “Warburg effect”, cancer cells also actively reprogram amino acid metabolism to satisfy high nutritional demands in a nutrient-poor environment. In the glucose–alanine cycle, exogenous alanine taken up by hepatocytes is converted to pyruvate via glutamic-pyruvic transaminases (GPTs). However, the precise role of the glucose–alanine cycle in hepatocellular carcinoma (HCC) remains elusive. The current study revealed that alanine, as an alternative energy source, induced the metabolic reprogramming of HCC cells via activation of the downstream glucose–alanine cycle and thus promoted HCC growth in nutrient-depleted conditions. Further overexpression and loss-of-function studies indicated that GPT1 was an essential regulator for alanine-supplemented HCC growth. Combining molecular docking and metabolomics analyses, our study further identified a naturally occurring alkaloid, berberine (BBR), as the GPT1 inhibitor in HCC. Mechanically, BBR-mediated metabolic reprogramming of alanine-supplemented HCC via GPT1 suppression attenuated adenosine triphosphate (ATP) production and thus suppressed HCC growth. In conclusion, our study suggests that GPT1-mediated alanine–glucose conversion may be a potential molecular target for HCC therapy. Further demonstration of BBR-mediated metabolic reprogramming of HCC would contribute to the development of this Chinese medicine-derived compound as an adjuvant therapy for HCC.
Highlights
Hepatocellular carcinoma (HCC) is the most common primary hepatic malignancy with complex risk factors, and ranks third in worldwide causes of cancer-related deaths [1,2]
ASCT2 and GLUT1 were enhanced by GPT1-overexpressed MHCC97L cells (GPT1) overexpression (Figure 2C and Figure S4). These results indicated that GPT1 overexpression activated the glucose–alanine cycle of nutrient-deprived or low-nutrient-cultured HCC cells with alanine supplementation
We found that the exogenous addition of alanine, as an alternative energy resource, could induce the metabolic reprogramming of HCC cells via activating the downstream glucose–alanine cycle and promote HCC growth in nutrient-depleted conditions
Summary
Hepatocellular carcinoma (HCC) is the most common primary hepatic malignancy with complex risk factors, and ranks third in worldwide causes of cancer-related deaths [1,2]. As its mortality rate is similar to its incidence. There are three main conventional therapeutics for HCC: surgical resection, chemotherapy, and radiotherapy. Surgical resection is suitable for only a small number of HCC patients due to poor hepatic conditions at a late diagnosis. As the main therapies for HCC, chemotherapy and radiotherapy present serious side effects, such as hematological toxicity and liver and kidney dysfunction [3]. The increasing acquired resistance reduces the therapeutic efficacy of these two main therapies [4]. The development of more effective and less toxic therapeutic drugs is urgently needed
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